Sunday, April 20, 2014

The summer day on Okinawa Island of Japan was so warm that those
us who were there to teach had given up on going to the beach in the afternoon
and instead had decided to try some early morning tennis. On this particular early morning, a
distinguished scientist and friend had joined our group, and there he was
holding the ball and warming up for his serve.
As he tossed the ball up, he bent his body sideways and then back and
twisted upwards and finally had his racquet make contact with the ball, delivering
a pretty good serve.

I stood there marveling at how he had learned to serve this
way. He said: “Well, I learned on my
own, and despite lots of coaches who have tried to break it down and rebuild it,
I haven’t been able to change it much.”

Memories, like that of how to hit a tennis serve, can become
so persistent that the brain seems unable to change them. This, at the surface, may not appear that
important, as the cost is looking a little silly and not being able to do something
as efficiently as possible. But what if you
are traveling with family on a peaceful day and stop at a gas station, and
suddenly the smell of petroleum brings back memories of combat, paralyzing you
with fear? What if you are watching a
movie where the hero is climbing the face of a rock and when she reaches the
peak, she stands and looks down, and you find your knees shaking? Does the brain have a mechanism in place to rebuild
or even erase unwanted habits and fear-inducing memories?

Until about 15 years ago, it was generally assumed that when
the brain learns something new, the newly acquired memory is initially in a
labile state and can be readily changed, but after a short period of time
(hours), it becomes ‘consolidated’, meaning that it becomes resistant to
change. For example, when rats were
given a single pairing of a tone with a food-shock, this made it so that the next
time they heard that tone, they got scared and stopped moving. If a drug was given to them that disrupted
the molecular pathways that are involved in consolidation (protein synthesis
inhibitors), the next day when they heard the tone they were not scared of
it. However, the drug had to be given
soon after the animal’s first experience of the tone-shock pairing. If it was given even a few hours after the
first experience, it did not have much of an effect; the animal still feared
the tone. And so it seemed that once an
emotional or fear-inducing memory was acquired, there was little that could be done
to change it.

The basis for this idea was a century of work that had
described how memories form. Neurons
communicate with each other via their synapses, tiny junctions where one neuron
sends and receives messages from another neuron. Eric Kandel, a Columbia University neuroscientist,
had shown that short-term memories, things that last for a few minutes, are due
to transient changes to the synapse to make it more efficient, but these changes
were sustained only for a short period of time.
To make memories last, the changes at the synapse had be sustained indefinitely,
and this required manufacture of new proteins.
If the initial experience was strong enough, with passage of time these
new proteins were made by the neuron and the memory was maintained, apparently
becoming permanent.

But in the year 2000, Karim Nader, an Egyptian born
neuroscientist who was raised in Canada, made a discovery that completely
overturned this idea. He was working in
Joseph LeDoux’s laboratory in New York University where he took rats and gave
them a single pairing of a tone with a foot-shock, and indeed, the next day he
found that when they heard the tone, the rats froze in their tracks (rats express
fear by ‘freezing’). However, right
after they heard this tone, he injected into their amygdala (a region of the
brain involved in storing fearful memories) a drug that inhibits protein
synthesis. Amazingly, he found that a
day later, when they heard the tone their fear was reduced by half (measured by
the time spent ‘freezing’). Interestingly,
if the drug was given without the reactivation of the memory (that is, on day 2
don’t play the tone), it had no effect. And if the animal heard the tone but 6 hours
later was given the drug, it still feared the tone the next day. So the key idea was that the fear-inducing memory
could be weakened if the drug was given right after the memory was reactivated,
but it could not be weakened if the drug was given alone, or if the memory was
reactivated but without the drug.

Unfortunately, protein synthesis inhibitors cannot safely be given
to humans, and so until recently, it was unclear whether this new understanding
could be applied to fear-inducing memories in people. In 2009, Merel Kindt and colleagues in
Amsterdam asked a few undergraduate students to look at a picture of a spider
and then a few seconds later played a loud sound, followed by a mild shock to
the hand. When the students heard the
loud sound, they had a startle reflex, producing an eye blink. They also showed them a picture of another
spider, followed by another loud sound, but no shock to the hand. So the students learned to fear the picture
of the 1st spider, but not the second. The amount of fear was measured by how they
reacted to the loud sound. Indeed, the
students feared the 1st spider more than the second. The students returned on Day 2, and Kindt
showed them the picture of the 1st spider, but did not shock
them. Right after this, they gave them a
drug called propranolol, which is often used to prevent stage fright, and works
to inhibit actions of norepinephrine. When
the students returned on the next day, they did not show fear of the
spider. Importantly, if they gave the drug
but did not show them the picture of the spider, the fear-inducing memory
remained.

So it seems possible that in humans, certain fear-inducing memories
can be weakened by a combination of reactivation of that memory and consumption
of certain drugs like propranolol. Later
work from the Kindt group showed that the key step is that during recall of the
memory, there must be a prediction error.
That is, during recall, the brain appears to predict that a bad thing is
going to happen (a shock), and if it does not happen, and the drug is present,
then the memory is weakened. Both the
prediction error and the presence of the drug seem to be required, as one
without the other is much less effective.

These approaches are now being studied for treatment of
PTSD. In a recent study, propranolol was
given to people who were involved in a serious car accident. Those people were less likely to develop PTSD
symptoms in the following 3 months compared to people who were given
placebo.

Notice, however, that all the successes have been on
weakening newly formed memories.
What about the old fear-inducing memories? The news there is less clear. Older memories may be less likely to be affected
when they are reactivated. Which brings me to one of my favorite quotes
from Margaret Thatcher, who was quoting her father when she said:

Watch your
thoughts for they become words.
Watch your words for they become actions.
Watch your actions for they become habits.
Watch your habits for they become your character.
And watch your character for it becomes your destiny.

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About Me

I was born in Iran and immigrated to the US at the age of 14. I was educated at Gonzaga University, University of Southern California, and finally MIT. I studied under the mentorship of Prof. Michael Arbib and Prof. Emilio Bizzi. I am currently Professor of Biomedical Engineering and Neuroscience, and the Director of the BME PhD Program at Johns Hopkins School of Medicine. I am a neuroscientist who uses mathematics to understand how the brain controls our movements.